A Murinized Bimagrumab Analogue Increases Skeletal Muscle Mass and Improves Cardiometabolic Remodelling in Experimental Hypertrophic Cardiomyopathy

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  FIGURE 1. Inhibition of myostatin/activin signalling with CDD866 increases skeletal muscle mass and improves glucose tolerance in R403Q mice with hypertrophic cardiomyopathy. A 4‐week CDD866 treatment induced skeletal muscle hypertrophy in R403Q mice, as evidenced by (A) EchoMRI showing increased body weight and lean mass with no change in fat mass, (B) micro‐CT showing increased lower hindlimb muscle volume and increased ex vivo weights of isolated skeletal muscles (pectoralis, triceps, quadriceps and gastrocnemius) and (C) quadriceps histology showing a shift towards larger myofibres with increased cross‐sectional area. (D) CDD866 increased forelimb grip strength and treadmill exercise tolerance, whereas resistance endurance was unchanged (Figures S5 and S6), suggesting that improved exercise tolerance is not explained solely by skeletal muscle endurance. (E) R403Q mice showed impaired glucose tolerance (oGTT), accompanied by nonsignificant increases in fasting insulin and HOMA‐IR, impaired oGTT was attenuated by CDD866. Data are mean ± SEM; n = 3–14. One‐way ANOVA with Bonferroni multiple comparisons tests (adjusted p value threshold of < 0.05) (oGTT: mixed‐effects model with Bonferroni…

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  FIGURE 2. Inhibition of myostatin/activin signalling with CDD866 improves cardiac phenotype and metabolism in R403Q mice with hypertrophic cardiomyopathy. Twenty‐four‐week‐old R403Q mice exhibited established HCM prior to treatment (Figure S2), and these hallmarks persisted after 4 weeks of placebo. (A) Echocardiography demonstrating LV hypertrophy, hypercontractility (fractional shortening) and diastolic dysfunction (E/A ratio and Em) (see Figure S11 for LV geometry indices). (B) Cardiac histopathology showing increased cardiomyocyte cross‐sectional area and fibrosis; both were improved by CDD866. (C) Ex vivo 13C substrate oxidation demonstrating a pathological shift in R403Q hearts from fatty acid oxidation towards glucose utilization with increased lactate production; CDD866 normalized substrate utilization and lactate output. Data are mean ± SEM; n = 4–9. One‐way ANOVA with Bonferroni multiple comparisons tests (adjusted p value threshold of < 0.05). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Representative images: haematoxylin–eosin (myocyte cross‐sectional area) and Masson's trichrome (fibrosis); scale bar, 50 μm.

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  FIGURE 3. Inhibition of myostatin/activin signalling with CDD866 restores cardiac transcriptomics deregulations in R403Q mice with hypertrophic cardiomyopathy. PCA (PC1 vs. PC2) showing separation of WT‐placebo and R403Q‐placebo, with R403Q‐CDD866 positioned between them, consistent with partial normalization of the R403Q transcriptional signature. Heatmap shows the union of leading‐edge genes from six metabolic gene sets coordinately downregulated in R403Q‐placebo vs. WT‐placebo and restored by CDD866 (FDR q < 0.05 for both comparisons): FA β‐ox (WP143), BCAA catabolism (R‐HSA‐70895), pyruvate metabolism (R‐HSA‐70268), TCA cycle (R‐HSA‐71403), oxidative phosphorylation (Hallmark) and ATP synthesis (GO:0015986).

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  FIGURE 4. Integrated transcriptomic and proteomic analysis. Heatmap of ingenuity pathway analysis (IPA) activation z‐scores for eight selected upstream regulators with concordant treatment‐associated directions in cardiac RNA‐seq and SomaScan proteomics. Regulators were selected for biological relevance from the 88 entries meeting nominal overlap p < 0.05 in both disease and treatment comparisons in each omics layer (Table S9). Regulators are grouped by broad biological role. Disease denotes R403Q‐placebo versus WT‐placebo; CDD866 denotes R403Q‐CDD866 versus R403Q‐placebo. Blue and red indicate negative and positive z‐scores, respectively, on a shared linear scale from −6 to +6. Outlined cells with bold numbers indicate |z| ≥ 2; smaller absolute scores represent weaker directional predictions. A dagger identifies an IPA directional bias flag in the RNA treatment export. Overlap p values were not adjusted for multiple testing. The panel presents selected examples of shared treatment direction, not an exhaustive regulator list or uniform reversal of disease predictions. Regulator activity is inferred from downstream target patterns and was not directly measured. The proteomic component is…

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  FIGURE 5. Graphical summary. Activin type II receptors (ActRII) inhibition improves skeletal muscle and cardiac phenotypes in experimental HCM. Four weeks of treatment with CDD866, a murinized bimagrumab analogue targeting ActRIIA/ActRIIB, increased skeletal muscle mass and grip strength and improved exercise performance in male R403Q mice with established hypertrophic cardiomyopathy (HCM). Treatment was accompanied by reduced LV hypertrophy and fibrosis, improved diastolic function and myocardial substrate utilization and opposing disease‐ and treatment‐associated changes in oxidative metabolic gene programmes identified by cardiac RNA‐seq GSEA. Solid arrows summarize treatment‐associated findings; they do not establish that skeletal muscle hypertrophy mediates the cardiac effects. The dashed box identifies potential contributors, including muscle–heart metabolic signalling, direct cardiac effects and other systemic effects, whose relative contributions remain unresolved. Other systemic effects may include adipose/BAT, endocrine and inflammatory mechanisms. GSEA, gene set enrichment analysis; HCM, hypertrophic cardiomyopathy; LV, left ventricular; Anatomical illustrations were generated…